The contribution of uniparental disomy to congenital development defects in children born to mothers at advanced childbearing age.

Most instances of maternal uniparental disomy (UPD) start as trisomies and, similar to the latter, show a significant increase of mean maternal age at delivery. To investigate the incidence of UPD in offspring of older mothers, we investigated two groups of patients: 1) 50 patients with unclassified developmental defects born to mothers 35 years or older at delivery were tested for UPD for all autosomes by means of microsatellite marker analysis; 2) The incidence of UPD versus other etiologies in correlation, with maternal age below versus 35 years and above at delivery was studied in patients investigated in our laboratory for maternal UPD 15 (Prader-Willi syndrome, PWS), paternal UPD 15 (Angelman syndrome, AS), and maternal UPD 7 (Silver-Russell syndrome, SRS). In group 1, four patients of 50 showed UPD for an autosome that clarified the etiology of their developmental problems: a 27-year-old woman with growth retardation and early puberty disclosed maternal heterodisomy 14; a 15-year-old girl revealed paternal isodisomy 15; a 6-year-old boy with suspected Smith-Lemli-Opitz syndrome was shown to have maternal heterodisomy 16 with additional mosaic partial trisomy 16(pter-p13); a 16-month-old girl with intrauterine growth retardation and a dysmorphic pattern revealed maternal heterodisomy 7. In group 2 the offspring of older mothers showed a clear increase of UPD compared with the mothers below 35 years at delivery. The binomial distribution gave P-values of 1.9 x 10(-10), 2.6 x 10(-4), and 0.01 for PWS, AS, and SRS, respectively. The correlation between increase of paternal UPD 15 with advanced maternal age might be explained by maternal non-disjunction leading to hypohaploid gamete (nullisomy) for chromosome 15 with subsequent or concomitant duplication of the paternal homologue (paternal isodisomy). The three UPD 15 AS cases with mothers older than 35 years at delivery revealed isodisomy, whereas the three cases from younger mothers showed heterodisomy. This study confirms the hypothesis that uniparental disomy is a not negligible cause of congenital developmental anomalies in children of older mothers.

Ginsburg C ，Fokstuen S ，Schinzel A 《american journal of medical genetics》

Cytogenetic and age-dependent risk factors associated with uniparental disomy 15.

Robinson WP ，Langlois S ，Schuffenhauer S ，Horsthemke B ，Michaelis RC ，Christian S ，Ledbetter DH ，Schinzel A ... -  《PRENATAL DIAGNOSIS》

Prenatal diagnosis of uniparental disomy 15 following trisomy 15 mosaicism.

Christian SL ，Smith AC ，Macha M ，Black SH ，Elder FF ，Johnson JM ，Resta RG ，Surti U ，Suslak L ，Verp MS ，Ledbetter DH ... -  《PRENATAL DIAGNOSIS》

Maternal disomy and Prader-Willi syndrome consistent with gamete complementation in a case of familial translocation (3;15) (p25;q11.2).

Park JP ，Moeschler JB ，Hani VH ，Hawk AB ，Belloni DR ，Noll WW ，Mohandas TK ... -  《american journal of medical genetics》

Advanced parental age in maternal uniparental disomy (UPD): implications for the mechanism of formation.

Kotzot D 《EUROPEAN JOURNAL OF HUMAN GENETICS》